A animal model of inherited movement disorders has been discovered in Sprague-Dawley rats. The mutant rats display sustained, involuntary twisting movements in the waking state. The movements are analogous to those that characterize torsion dystonia in man. In the rat model, the trait is inherited in an autosomal recessive pattern and no morphological lesions are apparent in routine histopathology. However, in a neurochemical survey of the extrapyramidal system of dystonic rats, elevated leels of crebellar norepinephrine have been found along with decreased numbers of Beta-adrenergic receptors. Glutamic acid decarboxylase activity in the deep cerebellar nuclei is also significantly increased in dystonic mutants and an increase in the number of dopamine receptors is evident in the corpus striatum. Preliminary psychoparmacological studies also indicate that components of the movement disorder can be modified by drug treatment and suggest a decreased sensitivity to dopamine agonists. The proposed studies are designed to systematically evaluate the function of the extrapyramidal system. Neurochemical techniques will be used to assess steady state levels and turnouver of neurotransmitters, receptor density and affinity, and enzyme activity in the noradrenergic, dopaminergic, chlolinergic and GABA-ergic systems. In addition behavioral observations will be made on animals given pharmacological treatments in order to test whether manipulation of transmitter systems displaying neurochemical alterations can effect changes in the movement disorder. Drugs will alsol be sought to precipitate dystonic movements prior to the natural onset of the disease. Surgical intervention will be used to examine the influeence of specific neuroanatomical structures on the disorder. Emphasis will be placed on sites where neurosurgical treatment in man has ameliorated dystonic symptoms. Based on the outcome of neurochemical and pharmacological studies, specialized neuroanatomical techniques, inccluding Golgi, Golgi-EM, and catechlamine histochemical fluorescence will be applied to search for neuropathologic defects at specific sites.